Vascular Modulation of Adipose function: Role of Endothelial Argonaute 1

Abstract

Among all individuals with Type 2 diabetes mellitus (T2DM), 80% are obese. The dramatic expansion of adipocytes can give rise to chronic hypoxia, poor blood perfusion, accumulation of pro‐inflammatory cytokines, all of which contribute to insulin resistance, key feature of T2DM. Lining the inner surface of microvessels, endothelial cells (ECs) respond to alterations in oxygen, metabolites, and growth factors to further modulate adipose function. However, the molecular and cellular mechanisms underlying the EC‐adipose crosstalk remain largely unknown and have recently attracted great research interests. In this study, we investigated the role of microvascular ECs in adipose function in the context of obesity and insulin resistance. Specifically, we examined the role of microRNA (miR)‐mediated gene regulation in the endothelial modulation of adipose function.We first used cross‐linking and immunoprecipitation sequencing (CLIP‐seq) to profile the miR targetome in ECs subjected to hypoxia, to which the EC response is often compromised in obesity. CLIP‐seq revealed a panel of angiogenic inhibitors, including thrombospondin‐1 (THBS1; which is positively associated with obesity and insulin resistance) were enriched in miR‐induced silencing complex in ECs under hypoxia. However, their expression was drastically suppressed in ECs by hypoxia. Ina murine T2DM model, mice with EC‐specific AGO1‐knockout (EC‐AGO1‐KO) exhibited a lean phenotype, with lower body weight and fasting glucose level and higher insulin sensitivity, as compared to their wild‐type littermates. The EC‐AGO1‐KO animals also had less body fat content, particularly in the subcutaneous and brown adipose tissues. Histological analysis and RNA‐seq demonstrated that EC‐AGO1‐KO possess higher angiogenic and browning activity and lower inflammation in the adipose depots. Overexpression of THBS1 abolished the protective effect of AGO1 in the subcutaneous tissues, suggesting that AGO1‐KO‐mediated metabolic benefit is in part through suppression of THBS1.Collectively, these results support a mechanism by which ECs, through AGO1‐mediated miR‐targetome modulate adipose function and metabolic states. Our study provides novel insights linking endothelial function and adipose tissue remodeling. Further, given that endothelial function is often compromised in T2DM, the molecular mechanisms underlying the endothelium‐adipocyte crosstalk may offer new approach to manage metabolic disruption associated with obesity and diabetes.Support or Funding InformationK99/R00HL122368This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.